Interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and oncostatin M (OSM) exert a broad range of similar biological activities through association of their receptors with the signal-transducing component gp130. Although it is known that cytokines trigger rapid tyrosine phosphorylation of a common set of cellular proteins as well as induction of several of the same early response genes, the mechanisms by which these genes are activated is not well understood. In this report we show that IL-6, LIF and OSM stimulate the assembly of protein complexes which recognize conserved sequences within the enhancers of two genes (IRF-1 and FcgRI) that are rapidly activated by these cytokines. These enhancers are known to be required for transcriptional induction of these genes by IFNg. Assembly of the DNA-binding protein complexes occurs within minutes after ligand addition and depends upon tyrosine phosphorylation. These complexes contain the p91 transcription factor, which is tyrosine phosphorylated in response to these cytokines. An additional tyrosine phosphorylated protein of Mr 93kDa can be co-immunoprecipitated with antibodies against p91. Thus, many cytokines activate p91 and, this supports the concept that sets of tyrosine phosphorylated proteins may be responsible for the cytokine regulated expression of early response genes. In contrast, immune complexes (IC) modulate the immune response in part by their ability to inhibit interferong (IFNg) dependent gene expression. Since many of the these genes require the tyrosine phosphorylation of p91, we examined the mechansims by which IC suppress IFNg induced expression of the Fcg receptor I gene (Fcgr1) in human monocytes. Preincubation of monocytes with IC resulted in a 70% reduction in steady state levels of RNA for the Fcgr1 gene. Treatment with IC resulted in no change in the IFNg receptor number. We previously described a DNA binding protein complex, termed FcRFg, that was rapidly activated by IFNg and which recognized the gamma response region (GRR) enhancer within the promoter of the Fcgr1 gene. Gel shift assays were used to measure the effects of IC treatment of monocytes on the IFNg induced activation of FcRFg. Monocytes were pretreated for 1 hr with IC and then exposed to IFNg for 5 min after which FcRFg was measured. There was a 70-80% reduction in IFNg induced formation of FcRFg. Kinetic analysis revealed that a 15 min pre-incubation with IC was all that was necessary for the inhbitory effect. Since one component of FcRFg is the p91 transcription factor which needs to be tyrosine phosphorylated for assembly of FcRFg, we next measured IFNg induced tyrosine phosphorylation of p91 in monocytes pretreated on IC. There was a marked reduction in the extent of tyrosine phosphorylation of p91 on these cells. Therefore, culture of human monocytes on IC inhibits IFNg induced expression of the Fcgr1 gene by preventing tyrosine phosphorylation of p91, thereby inhibiting the formation of the GRR binding complex, FcRFg.